Analogs of S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) will be prepared and enzymatically evaluated in an attempt to elucidate the structural requirements at the active site of various SAM- dependent methyltransferases. The enzymes of particular interest will be catechol-O-methyltransferase (COMT), phenethanolamine-N- methyltransferase (PNMT), histamine N-methyltransferase (HNMT) and hydroxyindole-O-methyltransferase (HIOMT), which are all important in the biosynthesis and/or metabolism of biogenic amines. Also of interest will be homocysteine-S-methyltransferase (HSMT), which is important in the biosynthesis of methionine and plus -RNA methylase, which is responsible for the methylation of plus -RNA. The structural modifications of SAM and SAH will involve changes in the acid portion, ribose moiety and the adenine portion. Of particular interest will be the replacement of the adenine moiety by various 6-substituted 1- deazapurines, 7-deazapurines, 2-azapurines and 8-azapurines. Evaluation of the SAM analogs as potential substrates or inhibitors and the SAH analogs as potential inhibitors for these enzymes will permit a more detailed delineation of the similarities or differences in the active sites of these enzymes.